Enantioselective direct α-amination of aldehydes via a photoredox mechanism: A strategy for asymmetric amine fragment coupling

Article abstract of DOI:10.1021/ja406181e

The direct, asymmetric α-amination of aldehydes has been accomplished via a combination of photoredox and organocatalysis. Photon-generated N-centered radicals undergo enantioselective α-addition to catalytically formed chiral enamines to directly produce stable α-amino aldehyde adducts bearing synthetically useful amine substitution patterns. Incorporation of a photolabile group on the amine precursor obviates the need to employ a photoredox catalyst in this transformation. Importantly, this photoinduced transformation allows direct and enantioselective access to α-amino aldehyde products that do not require postreaction manipulation.

Full text of DOI:10.1021/ja406181e

Communication
pubs.acs.org/JACS
Enantioselective Direct α‑Amination of Aldehydes via a Photoredox
Mechanism: A Strategy for Asymmetric Amine Fragment Coupling
Giuseppe Cecere, Christian M. Konig, Jennifer L. Alleva, and David W. C. MacMillan*
̈
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
ABSTRACT: The direct, asymmetric α-amination of
aldehydes has been accomplished via a combination of
photoredox and organocatalysis. Photon-generated N-
centered radicals undergo enantioselective α-addition to
catalytically formed chiral enamines to directly produce
stable α-amino aldehyde adducts bearing synthetically
useful amine substitution patterns. Incorporation of a
photolabile group on the amine precursor obviates the
need to employ a photoredox catalyst in this trans-
formation. Importantly, this photoinduced transformation
allows direct and enantioselective access to α-amino
aldehyde products that do not require postreaction
manipulation.
central goal in organic synthesis is the development of
Amethods to enantioselectively build C−N bonds within
complex molecular structures. In particular, aldehydes, acids, and
alcohols bearing α-amine substitution are widely distributed
among pharmaceutically active compounds, and their broad
representation has prompted the invention of a number of
Design plan. A detailed catalytic cycle for our proposed
catalysis strategies for stereogenic nitrogen installation.1,2 In this
context, α-amino aldehydes represent a valuable structural motif,
mainly because of their capacity to serve as versatile synthetic
handles en route to a diverse range of complex N-containing
synthons.3 However, the development of robust methods for the
asymmetric α-amination of aldehydes has been complicated by
the requirement for electrophilic sources of nitrogen along with
the need to circumvent postreaction racemization with relatively
acid- or base-sensitive products. As a consequence, traditional α-
carbonyl amination reactions often involve π-electrophile
addition pathways that culminate in the installation of hydrazinyl
or oxyamino substituents,4 a class of N-stereogenicity that must
be chemically modified (e.g., N−N or N−O reduction) prior to
synthetic elaboration (eq 1). In 2008, our lab introduced a
versatile platform for catalytic activation that we termed
photoredox organocatalysis. In a common embodiment,
electron-rich chiral enamines, derived from the condensation
of aldehydes and secondary amine catalysts, undergo rapid and
asymmetric aldehyde amination is presented in Scheme 1. We
postulated that an electrophilic N-based radical 1 might be
generated under mild conditions from an amine substrate 3
bearing a photolabile leaving group. While recent literature
suggests that N-centered radicals might be formed using
photoredox-active metal complexes,6 we envisioned that direct
access to such open-shell reaction partners might be best
accomplished using a traceless activation handle such as the
dinitrophenylsulfonyloxy (ODNs) group (a subunit that can be
chemoselectively triggered using a simple household lightbulb).
From the outset, it seemed plausible that an electrophilic
nitrogen radical such as 1 would rapidly undergo coupling with a
transiently generated π-rich enamine 2 (derived from the
condensation of an imidazolidinone catalyst with the aldehyde
coupling partner). Oxidation of the resulting three-π-electron α-
amino radical species 4 would then occur via single-electron
transfer (SET) to a second equivalent of the photoexcited amine
reagent 3*, a critical propagation step that would deliver iminium
ion 5 and simultaneously release the next round of the nitrogen
radical coupling partner.7 Hydrolysis of 5 would then
reconstitute the imidazolidinone catalyst and at the same time
deliver the enantioenriched α-amino aldehyde product. Notably,
despite growing interest in N-centered radicals as a source of
enantioselective coupling with electrophilic radical systems (e.g.,
5
•
•
CF3 , ArCH2 , etc.; eq 2). Here we demonstrate that this
“borrowed electron” catalysis strategy can be readily translated to
the enantioselective α-amination of aldehydes using N-centered
radicals (eq 3). As a critical design element, this open-shell
coupling mechanism allows for the direct generation of broadly
diverse α-amino aldehyde products that do not require
postreaction manipulation yet are stable to racemization.
Received: June 19, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja406181e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 1. Proposed Mechanism for Aldehyde α-Amination
Table 1. Initial Studies toward α-Amination of Aldehydes
a
b
c
entry catalyst temp (°C)
light source
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
6
rt
26 W CFL
none
30
0
91
--
6
rt
d
e
6
rt
26 W CFL
0
--
6
rt
LZC (300 nm)
26 W CFL
26 W CFL
26 W CFL
26 W CFL
26 W CFL
26 W CFL
38
40
47
65
82
77
72
90
75
92
78
88
86
86
91
7
rt
6
−15
−15
−15
−15
−15
−15
7
8
electrophilic nitrogen,8 few intermolecular amine coupling
processes have been reported,9 and indeed, no enantioselective
applications have been described to date.
9
10
10
11
11
26 W CFL
76
a
b
1
Our evaluation of the proposed aldehyde−amine coupling
began with exposure of 3-phenylpropionaldehyde to a series of
chiral amine catalysts and a large collection of N-based coupling
partners (Table 1). We were delighted to find that carbamate 3
incorporating a photolabile ODNs residue is competent to
produce the requisite heteroatom-centered radical upon
exposure to household light in the presence of catalyst 6 (30%
yield, 91% ee; entry 1).10 Presumably, photonic excitation of
amine 3 yields 3*, which readily undergoes single-electron
reduction and mesolysis of the weak N−O bond to yield the
desired amine-centered radical and ODNs anion. Initial
experiments using catalyst 6 confirmed that the reaction does
indeed require the use of light (entry 2 vs 1) and that a
continuous source of photons is required for reaction
propagation.11 Moreover, the use of a monochromatic light
source tuned to 300 nm (λmax = 292 nm for 3)10 resulted in
increased conversion and efficiency (38% yield, 90% ee, 6 h;
entry 4).12 These experiments provide additional evidence for
the participation of 3* in the photoredox process as described in
Scheme 1.
We next evaluated amine catalysts of varying steric demand,
with the supposition that higher enamine content13 and
increased exposure of the reactive π system would facilitate the
critical radical addition step. Indeed, experiments performed in
the presence of imidazolidinone catalyst 7, a system that
generally provides higher enamine content, exhibited improved
overall efficiency (40% yield; entry 5), albeit with lower levels of
stereocontrol (75% ee). Next, the effect of temperature on this α-
amination protocol was evaluated. A significant improvement in
the reaction yield was observed at subambient temperatures (47
vs 30%; entry 6 vs 1), presumably because of the capacity to
circumvent deleterious reduction of the carbamyl radical, a
pathway that would consume the amine reagent without
CFL = compact fluorescent light. Obtained by H NMR analysis
using methyl benzoate as an internal standard. Determined by chiral
HPLC analysis of the corresponding alcohol. Without 2,6-lutidine.
Carried out in a photobox equipped with 10 × Luzchem LZC-UVB.
c
d
e
productive C−N bond formation.14 Finally, during the course
of our optimization studies, we determined that the aminal C2
position on the imidazolidinone framework was susceptible to H-
atom abstraction by the N-centered radical, leading to
diminished reaction efficiency. This catalyst decomposition
pathway was suppressed via the design of a novel organocatalyst
framework wherein the C2 position incorporates a fully
substituted carbon stereocenter (catalysts 8−11; entries 8−
11).15 In particular, the use of imidazolidinone 11 provided the
desired α-amino aldehyde adduct with optimal levels of efficiency
and enantiocontrol (76% yield, 91% ee; entry 11).
It is notable that amine catalyst 11 was identified as the optimal
organocatalyst for this transformation, as it has not previously
been utilized in enamine- or iminium-based transformations. The
high levels of enantiocontrol observed in this study can be
rationalized on the basis of enamine olefin geometry and π-facial
selectivity. More specifically, density functional theory (DFT)
studies16 of the corresponding enamine intermediate DFT-12
(Figure 1) revealed that the E configuration of the four-π-
electron olefin system is preferred, as it positions the electron-
rich reaction site away from the fully substituted carbon center on
the imidazolidinone framework. This preferred enamine
geometry along with the m-ethyl arene orientation (as shown)
was further confirmed by 2D nuclear Overhauser effect
spectroscopy (NOESY) NMR studies.17
Reaction scope. With our optimal conditions in hand, we
examined the scope of this new enantioselective C−N bond-
forming protocol. This radical-based coupling is compatible with
B
dx.doi.org/10.1021/ja406181e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 3. Enantioselective α-Amination: Aldehyde Scope
Figure 1. DFT structure of the catalyst-derived enamine (DFT-12).
a variety of amine reaction partners adorned with an array of alkyl
motifs and carbamate protecting groups (71−79% yield, 86−
94% ee; Table 2). It is important to note that many of these novel
Table 2. Enantioselective α-Amination: Amine Scope
a
Stereochemistry assigned by chemical correlation or by analogy.
Determined by chiral HPLC analysis of the corresponding alcohol or
b
2-naphthoyl ester.
Moreover, this protocol provides direct asymmetric access to
synthetically valuable, configurationally stable α-amino aldehyde
adducts that can be readily isolated and purified via column
chromatography without further derivatization.
As a further demonstration of the synthetic utility of this
method, we illustrate representative procedures for the
conversion of these enantioenriched α-amino aldehyde adducts
to either β-amino alcohol or α-amino acid motifs (Scheme 2).
Scheme 2. Telescoped Syntheses of β-Amino Alcohols and α-
Amino Acids from Hydrocinnamaldehyde
a
Stereochemistry assigned by chemical correlation or by analogy.
Determined by chiral HPLC analysis of the corresponding alcohol.
b
amine reagents are readily accessed in two steps from N-methyl
hydroxylamine and are uniformly bench-stable, crystalline
solids.18 Moreover, the bisprotected N-Moc-N-MOM amine
reagent can be effectively used for α-amination of aldehydes with
excellent enantiocontrol (75% yield, 94% ee; entry 6). This
specific example represents an important expansion of the scope
of this method, offering a means to access orthogonally N,N-
protected α-amino aldehydes enantioselectively.
We next sought to establish the scope of the aldehyde coupling
partner in this transformation (Table 3). We were pleased to find
that these mild redox conditions accommodate a wide range of
substituents on the aldehyde component, including ethers,
amines, alkenes, and aromatic rings (71−79% yield, 88−91% ee;
entries 2−6). Moreover, excellent levels of enantiocontrol were
achieved with sterically demanding formyl substrates (67−72%
yield, 91−94% ee; entries 7 and 8). It should be noted that α-
dialkyl aldehyde systems are not useful substrates in this
transformation, as the imidazolidinone family of catalysts do
not readily condense with α-branched aldehydes. This is an
important catalyst design feature as it prevents postreaction
racemization with the products generated in Tables 2 and 3.
The crude product of the α-amination reaction (Table 2, entry 2)
could be directly converted to the corresponding β-amino
alcohol in good yield with complete stereofidelity. Alternatively,
direct oxidation with buffered KMnO4 afforded the Cbz-
protected N-methylphenylalanine with useful reaction efficiency
and retention of optical purity. We anticipate that this α-
amination/aldehyde derivatization strategy will find broad
application in the synthetic community as a facile means to
obtain rapid access to high-value nonproteogenic α-amino acids
and N-alkyl-α-amino acids.19−22
C
dx.doi.org/10.1021/ja406181e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Fu, Y.; Xie, M.; Liu, L.; Guo, Q.-X. J. Org. Chem. 2007, 72, 8025.
(h) Yuan, X.; Liu, K.; Li, C. J. Org. Chem. 2008, 73, 6166.
In summary, we have developed an organocatalytic photo-
redox-based approach to the asymmetric α-amination of
aldehydes via the direct coupling of functionalized nitrogen
and formyl precursors. This operationally facile process provides
ready access to complex N-substituted α-amino aldehydes and at
the same time offers a useful alternative to standard π-electron
addition approaches to carbonyl α-amination. Moreover, to the
best of our knowledge, this disclosure marks the first
demonstration of the use of N-based radicals as viable reagents
in a catalytic enantioselective transformation. We anticipate that
this α-amination method will prove widely useful in the synthesis
of complex target structures bearing chiral amine fragments.
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(10) For synthesis details and UV−vis spectra of the amine reagents,
see sections XI and XII in the Supporting Information (SI).
(11) The transformation did not undergo propagation upon removal
of the light source, implicating a photon-induced electron transfer event.
Moreover, generation of the N-centered radical required the presence of
the electron-rich enamine (Table 1, entry 3). More specifically, UV−vis
analysis of the radical precursor and the catalytically activated enamine
(generated separately and concurrently) clearly showed that dispro-
portionation of a charge transfer complex is not the mechanism for
carbamyl radical production (Scheme 1). Lastly, we determined that N−
O bond homolysis of 3 does not occur in the absence of an SET event.
(12) We chose to optimize this transformation using a household light
source in lieu of the slightly more efficient LZC system to allow
operational convenience for practitioners of this chemistry.
(13) The enamine concentration during the reaction was evaluated by
1H NMR analysis of the crude reaction mixture performed in CD3CN/
DMSO-d6.
ASSOCIATED CONTENT
■
S
* Supporting Information
Procedures, spectral data, and complete ref 16. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
dmacmill@princeton.edu
■
Notes
(14) 1H NMR analysis of the crude reaction mixture showed decreased
levels of MeNHCO2Me (10−15%) for couplings performed at −15 °C.
MeNHCO2Me can be formed from the corresponding radical by either
H-atom abstraction from the solvent or SET reduction to the amine
anion followed by protonation from the medium.
(15) For the synthesis of 11, see sections IV and V in the SI.
(16) DFT calculations were performed at the B3LYP/6-31G* level as
implemented in Gaussian 03: Frisch, M. J.; et al. Gaussian 03, revision
C.02; Gaussian, Inc.: Wallingford, CT, 2004.
(17) For NMR studies, see section IX in the SI.
(18) These amine reagents can be stored in the presence of moisture or
light at ambient temperatures without decomposition.
(19) (a) Sieber, S. A.; Marahiel, M. A. Chem. Rev. 2005, 105, 715.
(b) Vlieghe, P.; Lisowski, V.; Martinez, J.; Khrestchatisky, M. Drug
Discovery Today 2010, 15, 40.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NIGMS (R01 GM-
093213-03) and kind gifts from Merck, Amgen, and AbbVie.
G.C. is grateful for a Merck Overseas Postdoctoral Fellowship.
C.M.K. thanks the German Academic Exchange Service
(DAAD) for a postdoctoral fellowship. The authors thank E.
Mosconi for assistance in performing DFT calculations and C.
Kraml and N. Byrne (Lotus Separations, LLC) for their
development of preparatory supercritical-fluid chromatography
methods and gram-scale separation of the enantiomers of 11.
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J. Pharm. Exp. Ther. 1997, 280, 1147. (b) Harris, K. S.; Casey, J. L.;
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S.; Hughes, A. B.; Scanlon, D.; Foley, M. J. Biol. Chem. 2009, 284, 9361.
(c) Tulla-Puche, J.; Marcucci, E.; Prats-Alfonso, E.; Bayol-Puxan, N. R.;
Albericio, F. J. Med. Chem. 2009, 52, 834.
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dx.doi.org/10.1021/ja406181e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX